Diarrhea is the primary result of infection by noninvasive, enterotoxinogenic bacteria such as Vibrio cholerae and Escherichia coli. Several species of Gram-negative bacteria, including Salmonella typhimurium, have been demonstrated to produce cholera toxin-like heat-labile enterotoxins. However, the role of heat-labile enterotoxin in the pathogenesis of enteroinvasive bacteria belonging to the genus Salmonella is unknown. Since an enteroinvasive pathogen is exposed to different types of cells and tissues than a noninvasive enteropathogen, there is a possibility that enterotoxin has a larger role in Salmonella pathogenesis than simply to cause diarrhea. The role of heat-labile enterotoxin in the pathogenesis of S. typhimurium will be examined by comparing the pathogenicity of enterotoxin-negative (Tox-) mutants to the pathogenicity of the parental strain in mouse and rabbit model systems. Tox- mutants will be isolated by site-directed transposon-mediated mutagenesis. The ability of the mutant strains to elicit intestinal fluid secretion will be tested in ligated ileal segments of the rabbit. The invasive properties of the mutants will be tested by determining the LD50 values of the bacteria in mice, and by determining how readily the bacteria disseminate from ligated ileal segments of the rabbit. The murine response to Tox+ and Tox- salmonellae will be examined in detail by observing in vivo growth curves and the interaction with macrophages of Tox+ and Tox- bacteria, and the host immune response to Tox+ and Tox- bacteria.